Physicochemical Solubility of and Biological Sensitivity to Long-Chain Alcohols Determine the Cutoff Chain Length in Biological Activity

Abstract

The cutoff phenomenon associated with the effectiveness of long-chain alcohols in the induction of anesthesia is also observed for various antimicrobial activities, although the mechanism has remained unknown for over eight decades. The minimum inhibitory concentrations at 25°C for budding yeast growth exponentially decreased with increasing chain length of n-alcohols (C 2-C 12), whereas alcohols $C 13 lost the inhibitory effect. Thus, growth inhibition by n-alcohols obeys the Meyer-Overton correlation up to C 12 and exhibits a cutoff phenomenon. The densities of n-alcohols are low, and the melting point and hydrophobicity increase with chain length. C 13 and C 14 inhibited yeast growth at 39.8°C, above their melting points. Alcohols #C 14 inhibited thermophilic bacterial growth at 50°C, whereas C 16 inhibited it at 67.5°C, above their melting points. Thus, the high melting points of long-chain alcohols contribute to the cutoff phenomenon. C 14 did not effectively inhibit yeast growth in a static culture at 39.8°C, in contrast to a shaking culture, in which the low density-dependent concentration gradient was eliminated. The duration of the transient growth inhibition of yeast by C 12 was prolonged by sonication, which prevented hydrophobic aggregation. Therefore, a nonuniform distribution owing to low density and high hydrophobicity contributes to the cutoff. C 14 inhibited the growth at 25°C of the pdr1,3,5 mutant, defective in multidrug efflux pumps, whereas C 12 did not inhibit the growth of yeast overexpressing PDR5, indicating that the sensitivity to long-chain alcohols contributed to the cutoff. A balance between the physicochemical solubility of and the biological sensitivity to long-chain alcohols determines the cutoff chain length.

Time-course of host cell transcription during the HTLV-1 transcriptional burst

“…Tax expression impairs the functions of p53 [28], causes genome instability, induces double-strand DNA breaks, and inhibits DNA damage-response pathways [5,[29][30][31][32]. HBZ opposes many functions of Tax including proviral transcription, likely mediated by its interactions with the transcription factors CREB, c-JUN and CBP/p300, and by suppression of NF-κB [33][34][35][36][37]. The mechanisms of the pleiotropic effects of HTLV-1 proviral expression remain unclear, and while many important findings have been made with tax-transfected cell lines or long-term in vitro transformed cell lines, it is a long-standing question how these observations apply to untransformed, naturally-infected T-cells.…”

Antimalarial Quinacrine and Chloroquine Lose Their Activity by Decreasing Cationic Amphiphilic Structure with a Slight Decrease in pH

“…We have reported that the low solubility of long-chain alcohols is responsible for the paradox, thereby resulting in simplification of the SAR without using the presumptive pocket in proteins. 43 The MICs of QC and CQ decreased exponentially with increases in logD from pH 5 to 8 (Figures 4A and 7A). This result indicates that the same compound with various lipophilicities obeys the Meyer− Overton correlation, thereby avoiding complicated interpretations due to various structures.…”

“…This is a prototype for the structure–activity relationship (SAR) in which the biological potency of various drugs increases exponentially with lipophilicity/hydrophobicity, although whether drugs target lipids or proteins because of the cutoff paradox of long-chain alcohols remains controversial. We have reported that the low solubility of long-chain alcohols is responsible for the paradox, thereby resulting in simplification of the SAR without using the presumptive pocket in proteins . The MICs of QC and CQ decreased exponentially with increases in logD from pH 5 to 8 (Figures A and A).…”

“…The minimum inhibitory concentration (MIC) of yeast was determined as described previously . Logarithmic BY4741 cells were mixed with YPD (0.1 M; pH 5.1, 6, 7, 7.5, or 8.1) containing 2% or 8% glucose at a final OD 600 of 0.05, and then 100 μL (1.25 × 10 5 cells) was dispensed into 96-well microtiter plates (Corning, Corning, NY).…”

“…The minimum inhibitory concentration (MIC) of yeast was determined as described previously. 43 Logarithmic BY4741 cells were mixed with YPD (0.1 M; pH 5.1, 6, 7, 7.5, or 8.1) containing 2% or 8% glucose at a final OD 600 of 0.05, and then 100 μL (1.25 × 10 5 cells) was dispensed into 96-well microtiter plates (Corning, Corning, NY). QC was added directly to the cell suspensions; 2-fold serial dilutions were performed in the wells, and the plates were incubated at 25 °C for 48 h. The MIC was the lowest concentration that completely inhibited microbial growth, as judged by visual observation.…”